Genetic Variant NM_031960.3:c.227A>T (chr17-41097858-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_031960.3(KRTAP4-8):c.227A>T(p.Lys76Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K76R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000023 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRTAP4-8
NM_031960.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.66

Publications

2 publications found

Variant links:

Genes affected

KRTAP4-8 (HGNC:17230): (keratin associated protein 4-8) Involved in aging and hair cycle. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

KRTAP4-8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.087798655).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031960.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	NM_031960.3	MANE Select	c.227A>T	p.Lys76Met	missense	Exon 1 of 1	NP_114166.1	Q9BYQ9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRTAP4-8	ENST00000333822.5	TSL:6 MANE Select	c.227A>T	p.Lys76Met	missense	Exon 1 of 1	ENSP00000328444.4	Q9BYQ9

Frequencies

GnomAD3 genomes

AF:

0.0000259

AC:

AN:

38600

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000555

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000232

AC:

AN:

1206596

Hom.:

Cov.:

162

AF XY:

0.0000218

AC XY:

AN XY:

595152

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000122

AC:

AN:

24616

American (AMR)

AF:

0.0000318

AC:

AN:

31488

Ashkenazi Jewish (ASJ)

AF:

0.000164

AC:

AN:

18280

East Asian (EAS)

AF:

0.0000364

AC:

AN:

27480

South Asian (SAS)

AF:

0.00

AC:

AN:

61298

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4046

European-Non Finnish (NFE)

AF:

0.0000208

AC:

AN:

959916

Other (OTH)

AF:

0.00

AC:

AN:

45822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.277

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000259

AC:

AN:

38660

Hom.:

Cov.:

AF XY:

0.0000518

AC XY:

AN XY:

19320

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

8908

American (AMR)

AF:

0.00

AC:

AN:

4068

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

850

East Asian (EAS)

AF:

0.00

AC:

AN:

2142

South Asian (SAS)

AF:

0.00

AC:

AN:

1718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0000555

AC:

AN:

18032

Other (OTH)

AF:

0.00

AC:

AN:

518

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.0

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.015

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.10

M_CAP

Benign

0.0015

MetaRNN

Benign

0.088

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.4

PhyloP100

-3.7

PrimateAI

Benign

0.19

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.034

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.022

Polyphen

0.73

Vest4

0.18

MutPred

0.50

Loss of methylation at K76 (P = 2e-04)

MVP

0.072

MPC

0.12

ClinPred

0.71

GERP RS

-0.34

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.15

gMVP

0.060

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over